Inhibition, i.e. the ability to withhold or attenuate an action or a thought, is of central importance in the regulation of behavior. Inhibitory deficits are key features of Bipolar Disorder (BD) and substance abuse disorders, including methamphetamine (MA) dependence. BD is one of the leading causes of disability worldwide, with an estimated cost of 96 million lost workdays and 14 billion dollars in salary per year in the United States alone. Although comorbid drug abuse has been reported to occur in a majority of BD individuals and is associated with more severe psychiatric symptoms and worse treatment outcome, most research studies and clinical trials involving BD have excluded subjects with a history of drug abuse. The objective of the current project is to examine the effect of both MA dependence and BD on deficits in inhibition using a novel human open field paradigm that we have developed in our lab. The assessment of inhibitory failure in BD individuals with concurrent MA dependence will enable the development of a model that may be used to predict novel treatments for these pathologies and help to identify the neural substrates underlying these disorders. Inhibitory deficits manifest as increased hyperactivity, perseverative behavior, and symptoms characterized by impulsivity, including increased responses to novelty. The first aim of this project will assess the effect of MA and BD on these behaviors in individuals placed into a novel room where locomotor activity, perseverative motor responses, and interactions with novel objects are quantified. Based on evidence for activation/sensitization of the dopaminergic system in the basal ganglia and damage to the prefrontal cortex, a region of the brain that mediates inhibition of behavior, we predict the most severe inhibitory deficits will be observed in BD individuals with a chronic history of MA dependence. The second aim of our project will examine the relationship between the clinical assessment of mania and deficits in inhibition in our human open field paradigm. We predict that increased manic symptoms, as measured by the Young Mania Rating Scale, will show a significant correlation with increased inhibitory deficits. PUBLIC HEALTH RELEVANCE: Our understanding and treatment of BD and the effects of concurrent drug dependence will greatly benefit from the development of a human model of the behavior dysfunction that occurs in this population. This project will improve our understanding of the etiology and pathology of BD and uses a paradigm that can help to diagnose and test treatments for the mood and substance abuse disorders.